{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Members of the FXYD family, in particular FXYD6 and FXYD2, are important tissue‐specific regulators of the Na⁺,K⁺‐ATPase that adjust its ion‐transport kinetics and trafficking to meet local physiological needs. FXYD6 is highly expressed in the central nervous system and sensory epithelia, where it associates with the Na⁺,K⁺ pump to modify its apparent affinity for Na⁺ and K⁺ and to accelerate pump turnover rates, thereby contributing to the generation and maintenance of critical ion gradients in neurons and in the inner ear (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " In the inner ear, FXYD6 is localized to epithelia that border the endolymphatic space, suggesting a role in regulating endolymph composition and thereby contributing to proper auditory function. Furthermore, proper dendritic mRNA localization of FXYD6 is important for synaptic development and neuronal network maintenance. Altered expression of FXYD6 has also been implicated in disease; for instance, its up‐regulation is observed in hepatocellular carcinoma and its deregulation in osteosarcoma (through interactions with microRNAs such as miR‑137 and miR‑372‑3p) appears to affect tumor cell proliferation and migration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": " Additionally, genetic studies have explored the potential link between FXYD6 and neuropsychiatric disorders such as schizophrenia"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", although the findings have not been entirely consistent. In contrast, FXYD2 is predominantly expressed in renal epithelial cells, where it modulates Na⁺,K⁺-ATPase activity by altering the local membrane electrostatics near the ion binding sites, thereby ensuring proper ion homeostasis in the kidney."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Collectively, these findings underscore the diverse yet critical roles of FXYD6 and FXYD2 in adjusting Na⁺,K⁺-ATPase functions to the specific demands of different tissues, with implications in sensory physiology, neuronal function, cancer progression, and renal ion transport.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Benjamin Delprat, Danièle Schaer, Sophie Roy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FXYD6 is a novel regulator of Na,K-ATPase expressed in the inner ear."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M609872200"}], "href": "https://doi.org/10.1074/jbc.M609872200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17209044"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17209044"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Benjamin Delprat, Jean-Luc Puel, Käthi Geering "}, {"type": "b", "children": [{"type": "t", "text": "Dynamic expression of FXYD6 in the inner ear suggests a role of the protein in endolymph homeostasis and neuronal activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Dyn (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/dvdy.21269"}], "href": "https://doi.org/10.1002/dvdy.21269"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17676640"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17676640"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Nobuyuki Shiina, Kazuhiko Yamaguchi, Makio Tokunaga "}, {"type": "b", "children": [{"type": "t", "text": "RNG105 deficiency impairs the dendritic localization of mRNAs for Na+/K+ ATPase subunit isoforms and leads to the degeneration of neuronal networks."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.6386-09.2010"}], "href": "https://doi.org/10.1523/JNEUROSCI.6386-09.2010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20861386"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20861386"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Dylan J Meyer, Sharan Bijlani, Marilina de Sautu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FXYD protein isoforms differentially modulate human Na/K pump function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Gen Physiol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1085/jgp.202012660"}], "href": "https://doi.org/10.1085/jgp.202012660"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33231612"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33231612"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Qian Gao, Xiongfei Chen, Hongxia Duan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FXYD6: a novel therapeutic target toward hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Protein Cell (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s13238-014-0045-0"}], "href": "https://doi.org/10.1007/s13238-014-0045-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24715268"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24715268"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Zheng-Min Li, Hong-Yan Zhang, Yu-Xue Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-137 is downregulated in human osteosarcoma and regulates cell proliferation and migration through targeting FXYD6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Drug Target (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3109/1061186X.2015.1057149"}], "href": "https://doi.org/10.3109/1061186X.2015.1057149"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26302771"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26302771"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "S-Y Xu, P-F Xu, T-T Gao "}, {"type": "b", "children": [{"type": "t", "text": "MiR-372-3p inhibits the growth and metastasis of osteosarcoma cells by targeting FXYD6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Rev Med Pharmacol Sci (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.26355/eurrev_201801_14101"}], "href": "https://doi.org/10.26355/eurrev_201801_14101"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29364472"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29364472"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Khalid Choudhury, Andrew McQuillin, Vinay Puri, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A genetic association study of chromosome 11q22-24 in two different samples implicates the FXYD6 gene, encoding phosphohippolin, in susceptibility to schizophrenia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/513475"}], "href": "https://doi.org/10.1086/513475"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17357072"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17357072"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Xiao-Min Gong, Yi Ding, Jinghua Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure of the Na,K-ATPase regulatory protein FXYD2b in micelles: implications for membrane-water interfacial arginines."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbamem.2014.04.021"}], "href": "https://doi.org/10.1016/j.bbamem.2014.04.021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24794573"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24794573"}]}]}]}